Exposure to repeated stress and trauma during childhood produces a cascade of molecular and cellular events that has the potential to exert enduring effects on brain development. These changes may be responsible for the development of depression, posttraumatic stress disorder (PTSD) and increased vulnerability to substance use and addiction. Study 1 will test the hypotheses that both PTSD and recurrent major depression mediate the association between childhood traumatic stress and increased risk for substance abuse. This study will also test the hypothesis that a functional polymorphism in the MAO-A promoter, which produces low levels of MAO-A activity will be associated with increased vulnerability to the adverse effects of childhood traumatic stress on drug use. These hypotheses will be tested in a sample of 20-25 year olds (n=500) who either have no history of exposure to childhood abuse or who have had a history of exposure to childhood abuse that fulfills the A(1) A(2) criteria for PTSD. Study 2 will test the hypotheses that exposure to chronic childhood traumatic stress effects the morphology, neuronal integrity and paramagnetic properties of the cerebellar vermis, and that cerebellar vermal abnormalities will be associated with enhanced risk for substance abuse. Three groups of subjects (30 per group) will be identified from the first study. Subjects will either have: (1) had no history of exposure to child abuse trauma; (2) childhood traumatic stress, and PTSD; or (3) childhood traumatic stress and recurrent major depression. Subjects in the three groups will be matched for degree of substance use. Morphometric MRI, T2- relaxometry and proton-echo-planar-spectroscopic imaging will be used to test these hypotheses. These subjects will also receive a probe dose of methylphenidate and a repeat T2-RT scan to test the hypothesis that exposure to childhood traumatic stress enhances hemodynamic response to stimulant drugs in the striatum and cerebellar vermis. Study 3 will test the hypotheses that exposure to childhood traumatic stress produces an increased and more enduring corticotropic, noradrenergic and vasopressin response, (and decreased or delayed oxytocin response) to stress in the Trier Social Stress Test. Overall, these studies will provide new insight into the neurobiological effects of chronic childhood traumatic stress and new understanding of the potential for PTSD and depression to mediate, and MAO-A levels to moderate, the association between early stress and drug abuse. These studies will also pursue the novel hypotheses that stress induced alterations in the cerebellar vermis and in oxytocin release are related to risk for substance abuse in survivors of chronic childhood traumatic stress. PERFORMANCESITE(S) (organization,city, state) On McLean Hospital Campus: Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA 02478 Brain Imaging Center, McLean Hospital, Belmont, MA 02478 Developmental Psychopharmacology Laboraton], Mailman Research Center, McLean Hospital, Belmont, MA 02478 KEY PERSONNEL. See instructions. Usecontinuationpages as neededto providethe required information in the format shownbelow. StartwithPrincipalInvestigatorL. istallotherkeypersonnelin alphabeticaol rder,last namefirst. Name Organization Roleon Project Teicher, Martin H., M.D., Ph.D. McLean Hospital P.l./Program Director Andersen,Susan L., Ph.D. McLean Hospital Investigator, MRI Anderson, Carl M.,Ph.D. McLean Hospital Investigator, MRI Fourligkas, Nikos, Ph.D. McLean Hospital Investigator, Data Kim, Dennis, M.D. McLean Hospital Investigator, Clinical Navalta, Carryl, Ph.D. McLean Hospital Investigator, Clinical Polcari, Ann, Ph.D., R.N. McLean Hospital Investigator, Clinical Renshaw, Perry, M.D., Ph.D. McLean Hospital MRI Expert Samsen-Jain, Jacqueline, Ph.D. McLean Hospital Investigator, Clinical Wong, Dona Lee, Ph.D. McLean Hospital Investigator , Genetics DisclosurePermissionStatemenL Applicableto SBIPJSTTROnly. See instructions. [] Yes [] No PHS 398 (Rev. 05/01) Page 2 Form Page2 Principal Investigator/Program Director (Last, first, middle): Teicher, Martin The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page ................................................................................................................................................ 1 Description,